Buprenorphine is a semi-synthetic opioid derivative of thebaine that is used to treat opioid addiction in higher dosages (>2 mg), to control moderate acute pain in non-opioid-tolerant individuals in lower dosages (˜200 μg), and to control moderate chronic pain in dosages ranging from 20-70 μg/hour. It is available in a variety of formulations: SUBUTEX, SUBOXONE, ZUBSOLV (buprenorphine HCl and naloxine HCl; typically used for opioid addiction), TEMGESIC (sublingual tablets for moderate to severe pain), BUPRENEX (solutions for injection often used for acute pain in primary-care settings), NORSPAN and BUTRANS (transdermal preparations used for chronic pain).
As an opioid, buprenorphine lends itself to some uses for which it has not been approved by the drug regulatory agency of the country in which it is used (such as the U.S. FDA). One such off-label use (perhaps the most common) is the use of SUBUTEX or SUBOXONE, a formulation intended solely for the treatment of opioid abuse, in palliation of severe pain with no neuralgic component or when the neuralgia is otherwise treated, such as with pregabalin. Niche pain indications for which SUBUTEX or SUBOXONE may be a medication of choice include obstruction of the small bowel; continuous nasogastric suction; oesophageal fistula; malignancy in the head or neck; and other cases where the patient is unable to swallow or this is difficult. Additionally, SUBUTEX or SUBOXONE may be an interesting alternative to sustained-release opioids such as morphine (MS CONTIN) and oxycodone (TARGIN).
Furthermore, buprenorphine is somewhat sleep-inducing, and may be of particular help when pain leads to sleeplessness. Other prototypical opioid side-effects may prove beneficial in the management of chronic pain, such as its characteristic euphoria (to alleviate depression due to pain, or in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants), as well as its anxiolytic effects. These effects manifest themselves chiefly when buprenorphine is used in patients not tolerant to opioids; use of a partial agonist such as buprenorphine in those tolerant or dependent will simply lead to precipitated withdrawal (if a different opioid is used concomitantly) or relief of withdrawal (if used as monotherapy).
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. The main use of naltrexone is for the treatment of alcohol dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names REVIA and DEPADE. In some countries including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name VIVITROL.
Naloxone is an opioid antagonist used to counter the effects of opiate overdose, for example heroin or morphine. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. Naloxone is also experimentally used in the treatment of congenital insensitivity to pain with anhidrosis (CIPA), an extremely rare disorder (1 in 125 million) that renders one unable to feel pain, or differentiate temperatures. Naloxone is marketed under various trademarks including NARCAN, NALONE and NARCANTI.
Nalbuphine is a semi-synthetic opioid, available under the trade name of NUBAIN for the treatment of moderate to severe pain. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and deliver. Nalbuphine is a semi-synthetic opioid agonist-antagonist analgesic of the phenanthrene series, and is chemically related to the widely used opioid antagonists, naloxone and naltrexone, and the potent opioid analgesic, oxymorphone.    HAMADA, T., et a., in U.S. Pat. No. 8,273,889 B2, issued Sep. 25, 2012 disclose a method for producing 2-azaadamantane, which process includes cyclizing in the presence of an acid.    KALOTA, D. J., in U.S. Pat. No. 8,232,398 B2, issued Jul. 31, 2012 discloses a recycling process for increasing the yield of opiate alkaloid derivatives, by introducing at least one recycling step.    WANG, P. X., et al., in U.S. Pat. No. 8,080,661 B2, issued Dec. 20, 2011 disclose processes for the synthesis of tertiary amines by directed N-alkylation, co-mediated by an alkylating agent and a protic solvent or a mixture of a protic solvent and an aprotic solvent.    ALLEN, B. E., in U.S. Pat. No. 8,227,608 B2, issued Jul. 24, 2012 discloses processes for increasing the yield of opiate alkaloid derivatives.    JARVI, E. T., et al., in U.S. Pat. No. 8,293,906 B2, issued Oct. 23, 2013 disclose processes for the alkylation of norbuprenorphine with reduced impurity formation.    BENTLEY, K. W., in U.S. Pat. No. 3,433,791, issued Mar. 18, 1969 discloses endoethano nor-oripavines and nor-thebanes.    HUDSON, E. G., et al., in US Patent Publication 2010/0210843 A1, published Aug. 19, 2010 disclose a process for the reductive alkylation of normorphinans by a carboxaldehyde in the presence of a reducing agent.    HUANG, B-S. in US Patent Publication 2008/0125592 A1, published May 29, 2008 discloses a process for preparing oxymorphone, naltrexone and buprenorphine.    HUANG, B-S., in US Patent Publication 2012/0156290 A1, published Jun. 21, 2012 discloses a process for preparing oxymorphone, naltrexone, and buprenorphine.    ARCHER, N., et al., in PCT Publication WO 2013/050748 A2, published Apr. 11, 2013 disclose a process for preparing buprenorphine, comprising 0-demthylation followed by N-alkylation with cyclopropylmethyl bromide.
There remains a need for a process for the preparation of opioids which is suitable for large scale/commercial manufacture, preferably a process which has fewer steps and/or fewer distillations and/or fewer isolation steps than current processes; while maintaining high yields and/or high purity in the final product.